As people grow older they can develop sarcopenia, a condition where muscle mass and strength decline. Sarcopenia can seriously affect quality of life and is linked to higher rates of illness and death. We don’t yet fully understand the causes of sarcopenia, and there are currently no treatments. It can be challenging to carry out studies of potential treatments in humans, due to safety, length of time required (i.e. waiting for people to grow older) and great expense. This means that there is a great need for human in vitro models of muscle cell ageing for identifying potential therapeutic drugs or protective agents.
Dr Thomas Nicholson, Professor Prof Simon Jones, Dr Jack Sullivan, Dr Josh Price and Michael Macleod (University of Birmingham) were awarded MyAge Missing Link funding to test whether human muscle cells collected as a by-product of surgery, could be used as a model for muscle ageing in vitro.
The project is based on the concept of biological versus chronological age. Gene activity within cells can be altered by a process of DNA methylation, where tiny chemical tags are added to DNA molecules – this is known as epigenetic modification. The process starts from conception and importantly, the pattern of modification changes over the life course, which means it can be used to estimate a person’s (biological) age. By comparing a person’s biological age to their chronological age, it is possible to assess whether that individual is ageing relatively quickly or slowly.
Professor Jones and colleagues have recently shown for the first time that skeletal muscle tissue from patients with chronic liver disease is biologically older when compared to healthy age-matched control tissue (1). It is possible that accelerated biological ageing through epigenetic modifications could be one of the mechanisms underlying certain diseases.
The team worked with biobanked human muscle cells that had been isolated and cryopreserved from muscle tissue collected during orthopaedic surgery and consented for research. Samples came from about 20 individuals across a wide range of ages (18 – 87 years). The team differentiated these cells into muscle fibres and analysed epigenetic modifications in each sample. They found that the biobanked cells appear to retain many of the epigenetic characteristics of their donor, and remarkably the cellular DNA profile could independently predict muscle mass and muscle function parameters.
Dr Nicholson said, “We are incredibly fortunate to work within the Queen Elizabeth Hospital. As part of the National Institute for Health & Care Research (NIHR) Birmingham Biomedical Research Centre, we have a close relationship with clinicians and access to appropriately consented patient samples, which has really accelerated our progress.”
“Getting 20 cell lines established in a few weeks was a logistical challenge, especially when some recovered from cryo-preservation better than others, but Josh, Michael and I all worked together to get the job done. We’re an interdisciplinary team, starting with research nurses, surgeons in the operating theatre, the biobank, our own biomedical laboratory and Jack Sullivan, our bioinformatics expert”.
“We are now confident that our human primary myotubes can be used as an in vitro preclinical model of ageing. This model system will significantly increase the capacity to screen and identify novel therapeutics that slow or prevent the development of sarcopenia, through targeting biological ageing processes.”
“I’m excited about the next experimental steps and the insights that we hope to uncover from the very large dataset we’ve generated.”
Read more about the team’s research below.
1.Nicholson T, Dhaliwal A, Quinlan JI, Allen SL, Williams FR, Hazeldine J, McGee KC, Sullivan J, Breen L, Elsharkawy AM, Armstrong MJ, Jones SW, Greig CA, Lord JM. Accelerated aging of skeletal muscle and the immune system in patients with chronic liver disease. Exp Mol Med. 2024 Jul;56(7):1667-1681. Open access link to the article
Dr Thomas Nicholson, University of Birmingham